The UCLA Clinical Neurophysiology Program Project (CNP) consists of multidisciplinary investigations into the fundamental mechanisms of mesial temporal lobe epilepsy (MTLE) by a team of clinical and basic neuroscientists who have been working together for a number of years. The CNP is currently in its 43rd year of NIH funding, and has continued to take advantage of the unique opportunities offered by an epilepsy surgery facility to carry out parallel, reiterative, invasive research on patients with MTLE and on experimental animal models of this disorder. With this application, we will focus our efforts on pathological high frequency oscillations (pHFO), which we believe reflect the fundamental neuronal disturbances underlying epileptogenicity and epileptogenesis. Ripple oscillations (human 80-150Hz, rat 100-200 Hz) occur in normal hippocampus and parahippocampal structures but not dentate gyms. Fast Ripples (FR) (human 150-500, rat 200-500 Hz) are pathological events uniquely occurring in mesial temporal structures capable of generating spontaneous seizures, including the dentate gyrus. Pathological Ripples can also be recorded in the epileptogenic dentate gyrus. Both types of pHFO can be detected during epileptogenesis days to weeks before spontaneous seizures occur, and also are present at the initiation of spontaneous seizures. We hypothesize that epileptogenic cerebral injuries result in neuronal reorganization consisting of increased excitability within small groups of interconnected principal neurons which are pathologically synchronized by specific classes of physiologically and/or morphologically, abnormal interneurons. We will use pHFO to address this hypothesis with three tightly integrated subprojects designed to elucidate the neuronal substrates of these epileptogenic field potentials. In vitro and in vivo experiments in patients with MTLE and experimental animal models of this condition are proposed to: i) identify and characterize the principal neurons and subclasses of interneurons activated during pHFO;ii) examine the effects of ablation or stimulation of specific neurons on pHFO generation;iii) map the temporospatial relationships among pHFO generating areas within mesial temporal limbic structures;and iv) establish the importance of systems interactions by examining the effects of circuit disconnection on pHFO and seizure generation. We anticipate that identification of the specific neuronal substrates and characterization of the networks underlying pHFO and seizure generation will provide novel targets for future approaches to treatment, and prevention of epilepsy, and new strategies for diagnosis.